US6451814B1ExpiredUtilityA1
Heterocyclic β-3 adrenergic receptor agonists
Est. expiryJul 17, 2020(expired)· nominal 20-yr term from priority
A61P 3/10A61P 9/10A61P 27/06A61P 29/00C07D 211/46C07D 401/06C07D 211/58C07D 401/12C07D 409/14A61P 13/00C07D 409/06C07D 211/54C07D 211/60C07D 211/62A61P 1/00C07D 211/96C07D 417/04C07D 417/12
83
PatentIndex Score
19
Cited by
35
References
8
Claims
Abstract
This invention provides compounds of Formula I having the structureU, V, W, X, and Y are as defined hereinbefore,or a pharmaceutically acceptable salt thereof, which are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound of formula I having the structure
(a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, substituted with (R 1 ) m ;
(b) a phenyl ring substituted with (R 1 ) m ;
(c) a naphthyl ring substituted with (R 1 ) m ; or
(d) a phenyl fused heterocycle selected from the group consisting of
U is —OCH 2 — or a bond;
V is O or a bond;
W is O, S(O) a ; NR 2 , or NCOR 2 ;
X is SO 2 , CO, —(CH 2 ) b —, a bond, or Ar;
Y is —NR 3 R 4 , Het, Ar, alkyl of 1-8 carbon atoms, or —O(CH 2 ) d R 5 ;
R 1 is alkyl of 1-8, carbon atoms, alkenyl of 2-7 carbon atoms, —OR 6 , halogen, cyano, trifluoromethyl, —CO 2 R 6 , —CONR 6 R 7 , —NHCOR 6 , or NHSO 2 R 8 ;
R 2 is hydrogen, alkyl of 1-8 carbon atoms, or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
R 3 and R 4 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl group, —(CH 2 ) g R 9 , —(CH 2 ) h COR 9 , —(CH 2 ) j CR 10 R 11 (CH 2 ) j R 9 , or —(CH 2 ) k CONR 12 R 13 ; or R 3 and R 4 may be taken together together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 5 is hydrogen; alkyl of 1-8 carbon atoms optionally substituted by 1-3 substituents selected from hydroxy, halogen, and aryl; cycloalkyl of 1-8 carbon atoms; Ar or Het;
R 6 , R 7 , and R 8 are each, independently, hydrogen, or alkyl of 1-8 carbon atoms, or aryl of 6-10 carbon atoms;
R 9 is hydrogen; alkyl optionally substituted with 1-3 substitutents selected from hydroxy, halogen, and aryl; cycloalkyl of 3-8 carbon atoms; Ar, or Het;
R 10 and R 11 are each, independently, hydrogen, alkyl, or aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 10 and R 11 are taken together to form a spiro fused cycloalkyl ring of 3-8 carbon atoms;
R 12 and R 13 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 12 and R 13 are taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 14 is CO 2 R 15 or aryl optionally substituted with a 1-3 substituents selected from —OR 15 and cycioalkyloxy of 3-8 carbon atoms;
R 15 is alkyl of 1-8 carbon atoms or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms optionally mono-, di-, or tri-substituted with R 16 ;
Het is (a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, S, and N which may be optionally mono- or di-substituted with R 16 ; or (b) a heterocyclic ring system optionally mono- or di-substituted by R 16 containing a 5-6 membered heterocyclic ring fused to one or two carbocyclic or heterocyclic rings such that the heterocyclic ring system contains 1-4 heteroatoms selected from O, S, and N;
R 16 is aryl, halogen, alkyl of 1-8 carbon atoms, —OR 17 , cycloalkyl of 3-8 carbon atoms, trifluoromethyl, cyano, —CO 2 R 17 ,—CONR 17 R 18 , —SO 2 NR 17 R 18 , —NR 19 CONR 17 R 18 , —NR 17 R 18 , —NR 17 COR 18 , —NO 2 , —O(CH 2 ) p CO 2 R 17 , —OCONR 17 R 18 , —O(CH 2 ) q OR 17 , or a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from O, S, and N;
R 17 , R 18 , and R 19 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl moiety, or aryl optionally mono-, di-, or tri-substituted with halogen, cyano, nitro, hydroxy, alkyl of 1-8 carbon atoms, or alkoxy of 1-8 carbon atoms; or when R 17 and R 18 are contained on a common nitrogen, R 17 and R 18 may be taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S;
a=0-2;
b=1-6;
d=0-3;
g=0-6;
h=0-6;
j=0-6;
k=0-6;
m=0-2;
p=1-6;
q=1-6;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein
is
(a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, substituted with (R 1 ) m ;
(b) a phenyl ring substituted with (R 1 ) m ;
(c) a phenyl fused heterocycle selected from the group consisting of
U is —OCH 2 — or a bond;
V is O or a bond;
W is O, S(O) a ; or NR 2 ;
X is SO 2 , CO, —(CH 2 ) b —, a bond, or Ar;
Y is —NR 3 R 4 , Het, Ar, alkyl of 1-8 carbon atoms, or —O(CH 2 ) d R 5 ;
R 1 is alkyl of 1-8 carbon atoms, alkenyl of 2-7 carbon atoms, aryl of 6-10 carbon atoms, —OR 6 , cycloalkyl of 3-8 carbon atoms, halogen, cyano, trifluoromethyl, —CO 2 R 6 , —CONR 6 R 7 , —NHCOR 6 , NHSO 2 R 6 , —NR 6 CONR 7 R 8 , —NR 6 R 7 , alkenyl of 2-7 carbon atoms, S(O) a R 6 , NO 2 , —O(CH 2 ) e CO 2 R 6 , —OCONR 6 R 7 , —O(CH 2 ) f OR 6 , or a 5-6 membered heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, and N;
R 2 is hydrogen, alkyl of 1-8 carbon atoms, or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
R 3 and R 4 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl group, —(CH 2 ) g R 9 , —(CH 2 ) h COR 9 , —(CH 2 ) j CR 10 R 11 (CH 2 ) j R 9 , or —(CH 2 ) k CONR 12 R 13 ; or R 3 and R 4 may be taken together together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 5 is hydrogen; alkyl of 1-8 carbon atoms optionally substituted by 1-3 substituents selected from hydroxy, halogen, and aryl; cycloalkyl of 1-8 carbon atoms; Ar or Het;
R 6 , R 7 , and R 8 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, aryl of 6-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
R 9 is hydrogen; alkyl optionally substituted with 1-3 substitutents selected from hydroxy, halogen, and aryl; cycloalkyl of 3-8 carbon atoms; Ar, or Het;
R 10 and R 11 are each, independently, hydrogen, alkyl, or aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 10 and R 11 are taken together to form a spiro fused cycloalkyl ring of 3-8 carbon atoms;
R 12 and R 13 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 12 and R 13 are taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 14 is CO 2 R 15 or aryl optionally substituted with a 1-3 substituents selected from —OR 15 and cycloalkyloxy of 3-8 carbon atoms;
R 15 is alkyl of 1-8 carbon atoms or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms optionally mono-, di-, or tri-substituted with R 16 ;
Het is (a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, S, and N which may be optionally mono- or di-substituted with R 16 ; or (b) a heterocyclic ring system optionally mono- or di-substituted by R 16 containing a 5-6 membered heterocyclic ring fused to one or two carbocyclic or heterocyclic rings such that the heterocyclic ring system contains 1-4 heteroatoms selected from O, S, and N;
R 16 is aryl, halogen, alkyl of 1-8 carbon atoms, —OR 17 , cycloalkyl of 3-8 carbon atoms, trifluoromethyl, cyano, —CO 2 R 17 ,—CONR 17 R 18 , —SO 2 NR 17 R 18 , —NR 17 OR 18 , —NR 19 CONR 17 R 18 , —NR 17 R 18 , —NR 17 COR 18 , —S(O) n R 17 , —NO 2 , —O(CH 2 ) p CO 2 R 17 , —OCONR 17 R 18 , —O(CH 2 ) q OR 17 , or a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from O, S, and N;
R 17 , R 18 , and R 19 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl moiety, or aryl optionally mono-, di-, or tri-substituted with halogen, cyano, nitro, hydroxy, alkyl of 1-8 carbon atoms, or alkoxy of 1-8 carbon atoms; or when R 17 and R 18 are contained on a common nitrogen, R 17 and R 18 may be taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S;
a=0-2;
b=1-6;
d=0-3;
e=1-6;
f=1-6;
g=0-6;
h=0-6;
j=0-6;
k=0-6;
m=0-2;
n=0-2;
p=1-6;
q=1-6;
or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 , which is
a) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
b) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid cyclohexylamide;
c) 4-(4-{2-[(2S)-3-(4-Fluoro-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
d) 4-(4-{2-[(2S)-3-(2-Allyl-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
e) 4-(4-{2-[(2S)-3-(6-Amino-pyridin-3-yloxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
f) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [2-(3-methoxy-phenyl)-ethyl]-amide;
g) 4-(4-{2-[2-(3-Carbamoyl-4-hydroxy-phenyl)-2-hydroxy-ethylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
h) 4-[Acetyl-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenyl)-amino]-piperidine-1-carboxylic acid octylamide;
i) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid methylamide;
j) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid ethylamide;
k) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid isopropyl-amide;
l) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-cyclopentyl-propyl)-amide;
m) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (2,2,2-trifluoro-ethyl)-amide;
n) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid diethylamide;
o) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide;
p) 4-(4-{2-[(2S)-3-(2-Chloro-4-hydroxy-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
q) [4-(3-Cyclopentyloxy-4-methoxy-phenyl)-piperidin-1-yl]-[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-methanone;
r) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid amide;
s) 4-[4-(2-{(2S)-3-[4-(3-Ethyl-ureido)-phenoxy]-2-hydroxy-propylamino}-ethyl)-phenylamino]-piperidine-1-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide;
t) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,4-dichloro-benzylamide;
u) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 3,4-dichloro-benzylamide;
v) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-methanesulf onylamino-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
w) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-thiophen-2-yl-propyl)-amide;
x) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 3,5-difluoro-benzylamide;
y) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,3-dimethoxy-benzylamide;
z) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2-fluoro-benzylamide;
aa) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 3-fluoro-benzylamide;
bb) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-oxo-3-p-tolyl-propyl)-amide;
cc) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-p-tolyl-propyl)-amide;
dd) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide;
ee) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (2,2-diphenyl-ethyl)-amide;
ff) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,6-difluoro-benzylamide;
gg) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2-trifluoromethyl-benzylamide;
hh) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-pyrazol-1-yl-2-trifluoromethyl-benzylamide;
ii) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-methyl-butyl)-amide;
jj) 4-(4-{2-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
kk) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,5-difluoro-benzylamide;
ll) 5-[(S)-3-[[2-[4-[[1-[[[(2,5-Difluorophenyl)methyl]amino]carbonyl]-4-piperidinyl]amino]phenyl]ethyl]amino]-2-hydroxypropoxy]-2-hydroxybenzoic acid;
mm) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethoxy}-phenylamino)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
nn) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylsulfanyl)-piperidine-1-carboxylic acid phenylamide;
oo) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylsulfanyl)-piperidine-1-carboxylic acid hexylamide;
pp) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylsulfanyl)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
qq) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylsulfanyl)-piperidine-1-carboxylic acid (1-phenyl-cyclopentylmethyl)-amide;
rr) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid hexylamide;
ss) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
tt) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid (1-phenyl-cyclopentylmethyl)-amide;
uu) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid octylamide;
vv) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-3-methyl-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid octylamide;
ww) 4-(4-{2-[(2S)-3-(Benzo[1,3]dioxol-5-yloxy)-2-hydroxy-propylamino]-ethyl}-benzenesulfonyl)-piperidine-1-carboxylic acid octylamide;
xx) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-3-methanesulfonylamino-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,5-difluoro-benzylamide;
yy) 1-[4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-piperidine-4-carboxylic acid ethyl ester;
zz) 1-[4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-piperidine-4-carboxylic acid;
aaa) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
bbb) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenoxy)-piperidine-1-carboxylic acid octylamide;
ccc) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (8-fluoro-octyl)-amide;
ddd) 4-(4-{2-[(2S)2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenoxy)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
eee) 4-(4-{2-[2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [4-(3,4-dimethoxy-phenyl)-butyl]-amide;
fff) (4-{[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-amino}-phenoxy)-acetic acid;
ggg) 4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
hhh) 4-(4-{2-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
iii) 1-[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-piperidine-4-carboxylic acid ethyl ester;
jjj) 1-[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-piperidine-4-carboxylic acid;
kkk) 4-(4-{2-[(2S)-3-(3-Acetylamino-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
lll) 4-(4-{2-[(2S)-2-Hydroxy-3-(5-hydroxy-3,4-dihydro-2H-naphthalen-1-ylideneaminooxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
mmm) 4-(4-{2-[(2S)-3-(3-Fluoro-4-hydroxy-phenoxy)-2-hydroxy-propylamino]-ethyl]-phenylamino)-piperidine-1-carboxylic acid octylamide;
nnn) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-3-methanesulfonylamino-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid octylamide;
ooo) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-(3-hexyl-ureido)-benzylamide;
ppp) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-cyclohexyl-propyl)-amide;
qqq) 4-(4-{2-[(2S)-2-Hydroxy-3-(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-5-yloxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylicacid octylamide;
rrr) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxyaic acid cyclopentylmethyl-amide;
sss) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl4-phenylamino)-piperidine-1-carboxylic acid {2-[2-methoxy-4-(3-phenoxy-propoxy)-phenyl]-ethyl}-amide;
ttt) 4-(4-{2-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-ethoxy}-phenylamino)-piperidine-1-carboxylic acid octylamide;
uuu) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethoxy}-phenylamino)-piperidine-1-carboxylic acid octylamide;
vvv) Dimethyl-carbamic acid 4-(2-{[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-amino}-ethyl)-phenyl ester;
www) 4-(4-{2-[(2S)-2-Hydroxy-3-(3-methanesulfonylamino-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
xxx) 4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,5-difluoro-benzylamide;
yyy) 1-[[4-[[4-[2-[[(2R)-2-Hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]ethyl]phenyl]amino]-1-piperidinyl]carbonyl]-L-proline, methyl ester;
zzz) 1-[[4-[[4-[2-[[(2R)-2-Hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]ethyl]phenyl]amino]-1-piperidinyl]carbonyl]-3-piperidine carboxylic acid, ethyl ester;
aaaa) 4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]ethyl}-phenylamino)-piperidine-1-carboxylic acid 3-methoxy-benzylamide;
bbbb) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,4-difluoro-benzylamide;
cccc) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [2-(4-fluoro-phenylcarbamoyl)-ethyl]-amide;
dddd) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid {2-[(4-chloro-phenyl)-methyl-carbamoyl]-ethyl}-amide;
eeee) 4-(4-{2-[2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2-fluoro-4-hydroxy-benzylamide;
ffff) Dimethyl-carbamic acid 3-fluoro-4-({[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-amino}-methyl)-phenyl ester;
gggg) 4-(4-{2-[(2S)-2-Hydroxy-3-(3-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-fluoro-benzylamide;
hhhh) [3-Fluoro-4-[[[[4-[[4-[2-[[(S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]phenyl]amino]-1-piperidinyl]carbonyl]amino]methyl]phenoxy]acetic acid;
iiii) 4-(4-{2-[(2S)-2-Hydroxy-3-(3-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2-fluoro-4-hydroxy-benzylamide;
jjjj) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-amide;
kkkk) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (2-diethylcarbamoyl-ethyl)-amide;
llll) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid (3-morpholin-4-yl-3-oxo-propyl)-amide;
mmmm) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(1H-indol-2-yl)-methanone;
nnnn) 4-[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-pheroxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid octylamide;
oooo) 1-Hexyl-3-(4-[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-phenyl}-urea;
pppp) [4-(4-{2-[2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(5-methoxy-1H-indol-2-yl)-methanone;
qqqq) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(7-nitro-1H-indol-2-yl)-methanone;
rrrr) (5-Bromo-1H-indol-2-yl)-[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-methanone;
ssss) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(3-methoxy-benzo[b]thiophen-2-yl)-methanone;
tttt) N-{3-[(2S)-2-Hydroxy-3-(2-{4-[1-(3-methoxy-benzo[b]thiophene-2-carbonyl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-phenyl}-acetamide;
uuuu) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(1H-indol-3-yl)-methanone;
vvvv) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(3-methyl-thiophen-2-yl)-methanone;
wwww) 4-[(2S)-2-Hydroxy-3-(2-{4-[i-(3-methyl-thiophene-2-carbonyl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-1,3-dihydro-benzoimidazol-2-one;
xxxx) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-(1H-indazol-3-yl)-methanone;
yyyy) 1-[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-hexan-1-one;
zzzz) [(2S)-1-(4-Fuoro-benzenesulfonyl)-pyrrolidin-2-yl]-[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidin-1-yl]-methanone;
aaaaa) 4-[4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidine-1-carbonyl]-benzoic acid;
bbbbb) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylsulfanyl)-piperidin-1-yl]-(3-methyl-thiophen-2-yl)-methanone;
ccccc) [4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-benzenesulfonyl)-piperidin-1-yl]-(2-methyl-thiophen-3-yl)-methanone;
ddddd) 1-Hexyl-3-{4-[4-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-sulfonyl]-phenyl}-urea;
eeeee) 1-{4-[4-(4-{2-[(2S)-3-(4-Fluoro-phenoxy)-2-hydroxy-propylamino]-ethyl}-phenylamino)-piperidine-1-sulfonyl]-phenyl}-3-hexyl-urea;
fffff) 1-{4-[4-(4-{2-[3-(2-allyl-phenoxy)-2-hydroxy-propylamino]ethyl}-phenylamino)-piperidine-1-sulfonyl]-phenyl}-3-hexyl-urea;
ggggg) 4-[(2S)-2-Hydroxy-3-(2-{4-[1-(octane-1-sulfonyl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-phenol;
hhhhh) 4-[(2S)-2-Hydroxy-3-(2-{4-[1-(toluene-4-sulfonyl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-phenol;
iiiii) 4-[(2S)-2-Hydroxy-3-(2-{4-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-phenol;
jjjjj) N-(4-[4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-sulfonyl]-phenyl}-acetamide;
kkkkk) N-(5-{[4-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]ethyl}anilino)piperidin-1-yl]sulfonyl}-4-methyl-1,3-thiazol-2-yl)acetamide;
lllll) N-(2-Hydroxy-5-{(1R)-1-hydroxy-2-[2-(4-{1-[4-(3-octyl-ureido)-benzenesulfonyl]-piperidin-4-ylamino}-phenyl)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;
mmmmm) 4-[(2S)-2-Hydroxy-3-(2-{4-[1-(4-phenyl-thiazol-2-yl)-piperidin-4-ylamino]-phenyl}-ethylamino)-propoxy]-phenol;
nnnnn) (R)-N-{2-Hydroxy-5-[1-hydroxy-2-(2-{4-[1-(4-phenyl-thiazol-2-yl)-piperidin-4-ylamino]-phenyl}-ethylamino)-ethyl]-phenyl}-methanesulfonamide;
ooooo) N-(2-Hydroxy-5-{(1R)-1-hydroxy-2-[2-(4-{1-[4-(piperidine-1-sulfonyl)-phenyl]-piperidin-4-ylamino}-phenyl)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;
ppppp) 4-[4-(4-{2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl}-phenylamino)-piperidin-1-yl]-benzoic acid ethyl ester;
qqqqq) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 4-fluoro-benzyl ester;
rrrrr) 4-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethyl}-phenylamino)-piperidine-1-carboxylic acid 2,5-difluoro-benzyl ester
sssss) or a pharmaceutically acceptable salt thereof.
4. A method of treating hyperglycemia or metabolic disorders mediated by insulin resistance in a mammal in need thereof which comprises providing to said mammal, an effective amount of a compound of formula I having the structure
(a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, substituted with (R 1 ) m ;
(b) a phenyl ring substituted with (R 1 ) m ;
(c) a naphthyl ring substituted with (R 1 ) m ; or
(d) a phenyl fused heterocycle selected from the group consisting of
U is —OCH 2 — or a bond;
V is O or a bond;
W is O, S(O) a ; NR 2 , or NCOR 2 ;
X is SO 2 , CO, —(CH 2 ) b —, a bond, or Ar;
Y is —NR 3 R 4 , Het, Ar, alkyl of 1-8 carbon atoms, or —O(CH 2 ) d R 5 ;
R 1 is alkyl of 1-8 carbon atoms, alkenyl of 2-7 carbon atoms, —OR 6 , halogen, cyano, trifluoromethyl, —CO 2 R 6 , —CONR 6 R 7 , —NHCOR 6 , or NHSO 2 R 8 ;
R 2 is hydrogen, alkyl of 1-8 carbon atoms, or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
R 3 and R 4 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl group, —(CH 2 ) g R 9 , —(CH 2 ) h COR 9 , —(CH 2 ) j CR 10 R 11 (CH 2 ) j R 9 , or —(CH 2 ) k CONR 12 R 13 ; or R 3 and R 4 may be taken together together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 5 is hydrogen; alkyl of 1-8 carbon atoms optionally substituted by 1-3 substituents selected from hydroxy, halogen, and aryl; cycloalkyl of 1-8 carbon atoms; Ar or Het;
R 6 , R 7 , and R 8 are each, independently, hydrogen, or alkyl of 1-8 carbon atoms, or aryl of 6-10 carbon atoms;
R 9 is hydrogen; alkyl optionally substituted with 1-3 substitutents selected from hydroxy, halogen, and aryl; cycloalkyl of 3-8 carbon atoms; Ar, or Het;
R 10 and R 11 are each, independently, hydrogen, alkyl, or aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 10 and R 11 are taken together to form a spiro fused cycloalkyl ring of 3-8 carbon atoms;
R 12 and R 13 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 12 and R 13 are taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 14 is CO 2 R 15 or aryl optionally substituted with a 1-3 substituents selected from —OR 15 and cycloalkyloxy of 3-8 carbon atoms;
R 15 is alkyl of 1-8 carbon atoms or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms optionally mono-, di-, or tri-substituted with R 16 ;
Het is (a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, S, and N which may be optionally mono- or di-substituted with R 16 ; or (b) a heterocyclic ring system optionally mono- or di-substituted by R 16 containing a 5-6 membered heterocyclic ring fused to one or two carbocyclic or heterocyclic rings such that the heterocyclic ring system contains 1-4 heteroatoms selected from O, S, and N;
R 16 is aryl, halogen, alkyl of 1-8 carbon atoms, —OR 17 , cycloalkyl of 3-8 carbon atoms, trifluoromethyl, cyano, —CO 2 R 17 ,—CONR 17 R 18 , —SO 2 NR 17 R 18 , —NR 19 CONR 17 R 18 , —NR 17 R 18 , —NR 17 COR 18 , —NO 2 , —O(CH 2 ) p CO 2 R 17 , —OCONR 17 R 18 , —O(CH 2 ) q OR 17 , or a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from O, S, and N;
R 17 , R 18 , and R 19 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl moiety, or aryl optionally mono-, di-, or tri-substituted with halogen, cyano, nitro, hydroxy, alkyl of 1-8 carbon atoms, or alkoxy of 1-8 carbon atoms; or when R 17 and R 18 are contained on a common nitrogen, R 17 and R 18 may be taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S;
a=0-2;
b=1-6;
d=0-3;
g=0-6;
h=0-6;
j=0-6;
k=0-6;
m=0-2;
p=1-6;
q=1-6;
or a pharmaceutically acceptable salt thereof.
5. A method of modulating glucose levels in a mammal in need thereof which comprises providing to said mammal, an effective amount of a compound of formula I having the structure
(a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, substituted with (R 1 ) m ;
(b) a phenyl ring substituted with (R 1 ) m ;
(c) a naphthyl ring substituted with (R 1 ) m ; or
(d) a phenyl fused heterocycle selected from the group consisting of
U is —OCH 2 — or a bond;
V is O or a bond;
W is O, S(O) a ; NR 2 , or NCOR 2 ;
X is SO 2 , CO, —(CH 2 ) b —, a bond, or Ar;
Y is —NR 3 R 4 , Het, Ar, alkyl of 1-8 carbon atoms, or —O(CH 2 ) d R 5 ;
R 1 is alkyl of 1-8 carbon atoms, alkenyl of 2-7 carbon atoms, —OR 6 , halogen, cyano, trifluoromethyl, —CO 2 R 6 , —CONR 6 R 7 , —NHCOR 6 , or NHSO 2 R 8 ;
R 2 is hydrogen, alkyl of 1-8 carbon atoms, or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
R 3 and R 4 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl group, (CH2) g R 9 , —(CH 2 ) h COR 9 , —(CH 2 ) j CR 10 R 11 (CH 2 ) j R 9 , or —(CH 2 ) k CONR 12 R 13 ; or R 3 and R 4 may be taken together together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 5 is hydrogen; alkyl of 1-8 carbon atoms optionally substituted by 1-3 substituents selected from hydroxy, halogen, and aryl; cycloalkyl of 1-8 carbon atoms; Ar or Het;
R 6 , R 7 , and R 8 are each, independently, hydrogen, or alkyl of 1-8 carbon atoms, or aryl of 6-10 carbon atoms;
R 9 is hydrogen; alkyl optionally substituted with 1-3 substitutents selected from hydroxy, halogen, and aryl; cycloalkyl of 3-8 carbon atoms; Ar, or Het;
R 10 and R 11 are each, independently, hydrogen, alkyl, or aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 10 and R 11 are taken together to form a spiro fused cycloalkyl ring of 3-8 carbon atoms;
R 12 and R 13 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 12 and R 13 are taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 14 is CO 2 R 15 or aryl optionally substituted with a 1-3 substituents selected from —OR 15 and cycloalkyloxy of 3-8 carbon atoms;
R 15 is alkyl of 1-8 carbon atoms or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms optionally mono-, di-, or tri-substituted with R 16 ;
Het is (a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, S, and N which may be optionally mono- or di-substituted with R 16 ; or (b) a heterocyclic ring system optionally mono- or di-substituted by R 16 containing a 5-6 membered heterocyclic ring fused to one or two carbocyclic or heterocyclic rings such that the heterocyclic ring system contains 1-4 heteroatoms selected from O, S, and N;
R 16 is aryl, halogen, alkyl of 1-8 carbon atoms, —OR 17 , cycloalkyl of 3-8 carbon atoms, trifluoromethyl, cyano, —CO 2 R 17 ,—CONR 17 R 18 , —SO 2 NR 17 R 18 , —NR 19 CONR 17 R 18 , —NR 17 R 18 , —NR 17 COR 18 , —NO 2 , —O(CH 2 ) p CO 2 R 17 , —OCONR 17 R 18 , —O(CH 2 ) q OR 17 , or a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from O, S, and N;
R 17 , R 18 , and R 19 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl moiety, or aryl optionally mono-, di-, or tri-substituted with halogen, cyano, nitro, hydroxy, alkyl of 1-8 carbon atoms, or alkoxy of 1-8 carbon atoms; or when R 17 and R 18 are contained on a common nitrogen, R 17 and R 18 may be taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S;
a=0-2;
b=1-6;
d=0-3;
g=0-6;
h=0-6;
j=0-6;
k=0-6;
m=0-2;
p=1-6;
q=1-6;
or a pharmaceutically acceptable salt thereof.
6. A method of treating or inhibiting urinary incontinence in a mammal in need thereof which comprises providing to said mammal an effective amount of a compound of formula I having the structure
(a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, substituted with (R 1 ) m ;
(b) a phenyl ring substituted with (R 1 ) m ;
(c) a naphthyl ring substituted with (R 1 ) m ; or
(d) a phenyl fused heterocycle selected from the group consisting of
U is —OCH 2 — or a bond;
V is O or a bond;
W is O, S(O) a ; NR 2 , or NCOR 2 ;
X is SO 2 , CO, —(CH 2 ) b —, a bond, or Ar;
Y is —NR 3 R 4 , Het, Ar, alkyl of 1-8 carbon atoms, or —O(CH 2 ) d R 5
R 1 is alkyl of 1-8 carbon atoms, alkenyl of 2-7 carbon atoms, —OR 6 , halogen, cyano, trifluoromethyl, —CO 2 R 6 , —CONR 6 R 7 , —NHCOR 6 , or NHSO 2 R 8 ;
R 2 is hydrogen, alkyl of 1-8 carbon atoms, or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
R 3 and R 4 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl group, —(CH 2 ) g R 9 , —(CH 2 ) h COR 9 , —(CH 2 ) j CR 10 R 11 (CH 2 ) j R 9 , or —(CH 2 ) k CONR 12 R 13 ; or R 3 and R 4 may be taken together together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 5 is hydrogen; alkyl of 1-8 carbon atoms optionally substituted by 1-3 substituents selected from hydroxy, halogen, and aryl; cycloalkyl of 1-8 carbon atoms; Ar or Het;
R 6 , R 7 , and R 8 are each, independently, hydrogen, or alkyl of 1-8 carbon atoms, or aryl of 6-10 carbon atoms;
R 9 is hydrogen; alkyl optionally substituted with 1-3 substitutents selected from hydroxy, halogen, and aryl; cycloalkyl of 3-8 carbon atoms; Ar, or Het;
R 10 and R 11 are each, independently, hydrogen, alkyl, or aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 10 and R 11 are taken together to form a spiro fused cycloalkyl ring of 3-8 carbon atoms;
R 12 and R 13 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 12 and R 13 are taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 14 is CO 2 R 15 or aryl optionally substituted with a 1-3 substituents selected from —OR 15 and cycloalkyloxy of 3-8 carbon atoms;
R 15 is alkyl of 1-8 carbon atoms or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms optionally mono-, di-, or tri-substituted with R 16 ;
Het is (a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, S, and N which may be optionally mono- or di-substituted with R 16 ; or (b) a heterocyclic ring system optionally mono- or di-substituted by R 16 containing a 5-6 membered heterocyclic ring fused to one or two carbocyclic or heterocyclic rings such that the heterocyclic ring system contains 1-4 heteroatoms selected from O, S, and N;
R 16 is aryl, halogen, alkyl of 1-8 carbon atoms, —OR 17 , cycloalkyl of 3-8 carbon atoms, trifluoromethyl, cyano, —CO 2 R 17 ,—CONR 17 R 18 , —SO 2 NR 17 R 18 , —NR 19 CONR 17 R 18 , —NR 17 R 18 , —NR 17 COR 18 , —NO 2 , —O(CH 2 ) p CO 2 R 17 , —OCONR 17 R 18 , —O(CH 2 ) q OR 17 , or a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from O, S, and N;
R 17 , R 18 , and R 19 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl moiety, or aryl optionally mono-, di-, or tri-substituted with halogen, cyano, nitro, hydroxy, alkyl of 1-8 carbon atoms, or alkoxy of 1-8 carbon atoms; or when R 17 and R 18 are contained on a common nitrogen, R 17 and R 18 may be taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S;
a=0-2;
b=1-6;
d=0-3;
g=0-6;
h=0-6;
j=0-6;
k=0-6;
m=0-2;
p=1-6;
q=1-6;
or a pharmaceutically acceptable salt thereof.
7. A method of treating or inhibiting atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, or ocular hypertension in a mammal in need thereof, which comprises providing to said mammal an effective amount of a compound of formula I having the structure
(a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, substituted with (R 1 ) m ;
(b) a phenyl ring substituted with (R 1 ) m ;
(c) a naphthyl ring substituted with (R 1 ) m ; or
(d) a phenyl fused heterocycle selected from the group consisting of
U is —OCH 2 — or a bond;
V is O or a bond;
W is O, S(O) a ; NR 2 , or NCOR 2 ;
X is SO 2 , CO, —(CH 2 ) b —, a bond, or Ar;
Y is —NR 3 R 4 , Het, Ar, alkyl of 1-8 carbon atoms, or —O(CH 2 ) d R 5 ;
R 1 is alkyl of 1-8 carbon atoms, alkenyl of 2-7 carbon atoms, —OR 6 , halogen, cyano, trifluoromethyl, —CO 2 R 6 , —CONR 6 R 7 , —NHCOR 6 , or NHSO 2 R 8 ;
R 2 is hydrogen, alkyl of 1-8 carbon atoms, or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
R 3 and R 4 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl group, —(CH 2 ) g R 9 , —(CH 2 ) h COR 9 , —(CH 2 ) j CR 1 OR 11 (CH 2 ) j R 9 , or —(CH 2 ) k CONR 12 R 13 ; or R 3 and R 4 may be taken together together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 5 is hydrogen; alkyl of 1-8 carbon atoms optionally substituted by 1-3 substituents selected from hydroxy, halogen, and aryl; cycloalkyl of 1-8 carbon atoms; Ar or Het;
R 6 , R 7 , and R 8 are each, independently, hydrogen, or alkyl of 1-8 carbon atoms, or aryl of 6-10 carbon atoms;
R 9 is hydrogen; alkyl optionally substituted with 1-3 substitutents selected from hydroxy, halogen, and aryl; cycloalkyl of 3-8 carbon atoms; Ar, or Het;
R 10 and R 11 are each, independently, hydrogen, alkyl, or aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 10 and R 11 are taken together to form a spiro fused cycloalkyl ring of 3-8 carbon atoms;
R 12 and R 13 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 12 and R 13 are taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 14 is CO 2 R 15 or aryl optionally substituted with a 1-3 substituents selected from —OR 15 and cycloalkyloxy of 3-8 carbon atoms;
R 15 is alkyl of 1-8 carbon atoms or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms optionally mono-, di-, or tri-substituted with R 16 ;
Het is (a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, S, and N which may be optionally mono- or di-substituted with R 16 ; or (b) a heterocyclic ring system optionally mono- or di-substituted by R 16 containing a 5-6 membered heterocyclic ring fused to one or two carbocyclic or heterocyclic rings such that the heterocyclic ring system contains 1-4 heteroatoms selected from O, S, and N; R 16 is aryl, halogen, alkyl of 1-8 carbon atoms, —OR 17 , cycloalkyl of 3-8 carbon atoms, trifluoromethyl, cyano, —CO 2 R 17 ,—CONR 17 R 18 , —SO 2 NR 17 R 18 , —NR 19 CONR 17 R 18 , —NR 17 R 18 , —NR 17 COR 18 , —NO 2 , —O(CH 2 ) p CO 2 R 17 , —OCONR 17 R 18 , —O(CH 2 ) q OR 17 , or a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from O, S, and N;
R 17 , R 18 , and R 19 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl moiety, or aryl optionally mono-, di-, or tri-substituted with halogen, cyano, nitro, hydroxy, alkyl of 1-8 carbon atoms, or alkoxy of 1-8 carbon atoms; or when R 17 and R 18 are contained on a common nitrogen, R 17 and R 18 may be taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S;
a=0-2;
b=1-6;
d=0-3;
g=0-6;
h=0-6;
j=0-6;
k=0-6;
m=0-2;
p=1-6;
q=1-6;
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition which comprises a compound of formula I having the structure
(a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, substituted with (R 1 ) m ;
(b) a phenyl ring substituted with (R 1 ) m ;
(c) a naphthyl ring substituted with (R 1 ) m ; or
(d) a phenyl fused heterocycle selected from the group consisting of
U is —OCH 2 — or a bond;
V is O or a bond;
W is O, S(O) a ; NR 2 , or NCOR 2 ;
X is SO 2 , CO, —(CH 2 ) b —, a bond, or Ar;
Y is —NR 3 R 4 , Het, Ar, alkyl of 1-8 carbon atoms, or —O(CH 2 ) d R 5 ;
R 1 is alkyl of 1-8 carbon atoms, alkenyl of 2-7 carbon atoms, —OR 6 , halogen, cyano, trifluoromethyl, —CO 2 R 6 , —CONR 6 R 7 , —NHCOR 6 , or NHSO 2 R 8 ;
R 2 is hydrogen, alkyl of 1-8 carbon atoms, or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
R 3 and R 4 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl group, —(CH 2 ) g R 9 , —(CH 2 ) h COR 9 , —(CH 2 ) j CR 10 R 11 (CH 2 ) j R 9 , or —(CH 2 ) k CONR 12 R 13 ; or R 3 and R 4 may be taken together together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 5 is hydrogen; alkyl of 1-8 carbon atoms optionally substituted by 1-3 substituents selected from hydroxy, halogen, and aryl; cycloalkyl of 1-8 carbon atoms; Ar or Het;
R 6 , R 7 , and R 8 are each, independently, hydrogen, or alkyl of 1-8 carbon atoms, or aryl of 6-10 carbon atoms;
R 9 is hydrogen; alkyl optionally substituted with 1-3 substitutents selected from hydroxy, halogen, and aryl; cycloalkyl of 3-8 carbon atoms; Ar, or Het;
R 10 and R 11 are each, independently, hydrogen, alkyl, or aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 10 and R 11 are taken together to form a spiro fused cycloalkyl ring of 3-8 carbon atoms;
R 12 and R 13 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, aryl optionally substituted with alkyl of 1-8 carbon atoms or halogen; or R 12 and R 13 are taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S, and said heterocycle may optionally be substituted with R 14 ;
R 14 is CO 2 R 15 or aryl optionally substituted with a 1-3 substituents selected from —OR 15 and cycloalkyloxy of 3-8 carbon atoms;
R 15 is alkyl of 1-8 carbon atoms or arylalkyl having 1-8 carbon atoms in the alkyl moiety;
Ar is an aromatic ring system containing 1-2 carbocyclic aromatic rings having 6-10 carbon atoms optionally mono-, di-, or tri-substituted with R 16 ;
Het is (a) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, S, and N which may be optionally mono- or di-substituted with R 16 ; or (b) a heterocyclic ring system optionally mono- or di-substituted by R 16 containing a 5-6 membered heterocyclic ring fused to one or two carbocyclic or heterocyclic rings such that the heterocyclic ring system contains 1-4 heteroatoms selected from O, S, and N;
R 16 is aryl, halogen, alkyl of 1-8 carbon atoms, —OR 17 , cycloalkyl of 3-8 carbon atoms, trifluoromethyl, cyano, —CO 2 R 17 ,—CONR 17 R 18 , —SO 2 NR 17 R 18 , —NR 19 CONR 17 R 18 , —NR 17 R 18 , —NR 17 COR 18 , —NO 2 , —O(CH 2 ) p CO 2 R 17 , —OCONR 17 R 18 , —O(CH 2 ) q OR 17 , or a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from O, S, and N;
R 17 , R 18 , and R 19 are each, independently, hydrogen, alkyl of 1-8 carbon atoms, arylalkyl having 1-8 carbon atoms in the alkyl moiety, or aryl optionally mono-, di-, or tri-substituted with halogen, cyano, nitro, hydroxy, alkyl of 1-8 carbon atoms, or alkoxy of 1-8 carbon atoms; or when R 17 and R 18 are contained on a common nitrogen, R 17 and R 18 may be taken together with the nitrogen to which they are attached to form a 3-7 membered saturated heterocycle, which may optionally contain 1-2 additional heteroatoms selected from O and S;
a=0-2;
b=1-6;
d=0-3;
g=0-6;
h=0-6;
i=0-6;
k=0-6;
m=0-2;
p=1-6;
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